Between 33rd and 41st Avenue the street becomes decidedly more residential as it reaches its topographical summit. South of 41st, the street enters the Sunset neighbourhood and takes on a markedly Indo-Canadian character. The Punjabi Market district begins just north of 49th avenue; south of the Market the street again becomes predominantly residential.

At Main Street’s South-Vancouver intersection with Marine Drive its character becomes big-box commercial, notably including a Real Canadian Superstore supermarket. Between Marine and its southern terminus, Main Street’s neighbourhood is a highly-miscellaneous commercial mix including office space, manufacturing, and warehousing.

The north end of Main Street is located just west of the historic site of Hastings Mill, the nucleus around which Granville, later Vancouver, grew. In its earliest days, the intersection of Main and Hastings Streets was the centre of downtown Vancouver, boasting the city's central public library (now the Carnegie Centre) and — a few blocks away — the old City Hall. The intersection of Main and Hastings is now a local byword for the poverty, addictions, homelessness, and prostitution often associated with the Downtown Eastside.

The thoroughfare was originally named "Westminster Avenue", since it connects to New Westminster Road (now Kingsway). It received its present name in 1910[1] at the behest of local merchants, who thought that it bestowed a more cosmopolitan air to the neighbourhood.

Main Street was previously separated into two segments by False Creek, with a bascule bridge linking the two.[2] The two segments were joined together after the eastern section of False Creek was reclaimed for railway lands in the 1910s and 1920s.